Mechanism-Based Targeted Pancreatic Beta Cell Imaging and Therapy

ABSTRACT

Compositions for imaging pancreatic beta cells comprise chelator-antidiabetic agent conjugates and optionally chelated metals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is filed as a divisional of U.S. Ser. No. 10/942,615filed Sep. 16, 2004, which claims priority to U.S. Ser. No. 60/503,683filed Sep. 17, 2003.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

N/A

BACKGROUND OF THE INVENTION

In the United States, approximately 16 million people (6 percent of thepopulation) suffer from diabetes mellitus. Every year, about 800,000 newcases are diagnosed and another 6 million people remain unaware thatthey have the disease. Diabetes mellitus kills about 193,000 U.S.residents each year, and it is the seventh leading cause of all deathsand the sixth leading cause of all deaths caused by disease. There is asteady rise in children developing type 2 diabetes. In Canada, more than2.2 million residents (7 percent of the population) have diabetesmellitus, and the disease contributes to more than 25,000 deaths a year.

Adenocarcinoma of the pancreas is the fifth most common cause of cancerdeath in the United States. In the U.S., almost 45,000 people becomeaffected with pancreatic cancer every year. Cancer most often occurs inthe pancreatic head and often leads to biliary obstruction with aclinical presentation of painless jaundice. The 5 year survival rate forresectable patients is about 10% with a median survival of 12 to 18months. Unresectable patients live about 6 months. Both diseases areassociated with pancreatic function. Also, risk for pancreatic cancer isincreased in adult-onset diabetics.

In the pancreas, the Islets of Langerhans are composed of four celltypes, each of which synthesizes and secrets a distinct polypeptidehormone: insulin in the beta cell (60%), glucagon in the alpha cell(25%), somatostatin in the D cell (10%), and pancreatic polypeptide inthe F cell (5%). Beta cells are the major type of cells in the pancreas.Certain nutrients and growth factors can stimulate pancreatic beta-cellgrowth. However, the appropriate mitogenic signaling pathways inbeta-cells have been relatively undefined. This failure to define theseimportant signaling pathways is due at least in part to a lack ofeffective imaging technologies.

The current status of imaging in pancreatic diseases has been recentlyreviewed by Kaira et al. Journal of Computer Assisted Tomography26:661-675. The reviewed technologies include CT, MRI, EUS and PETscans.

SUMMARY

The present disclosure addresses at least in part some deficiencies inthe prior art by providing novel DTPA-antidiabetic conjugates useful forimaging beta-cell function. Through binding of radiolabeled conjugates,such as ^(99m)Tc-DTPA-antidiabetic conjugates, for example, topancreatic beta receptors, detectable by gamma scintigraphy, pancreaticfunction is monitored. Four DTPA-antidiabetic conjugates have beensynthesized and evaluated. Animal studies have shown thatDTPA-nateglinide and DTPA-glipizide are able to selectively imagepancreatic beta cells with no acute toxicity at the given doses. Theseagents are labeled with isotopes in order to assess beta cell functionin diabetic or insulinoma patients both pre- and post-treatment. Thesecompositions and methods are useful to provide early diagnosis as wellas monitoring of response of pancreatic disease during treatment.

The present invention may be described in certain embodiments thereforeas a composition comprising an antidiabetic agent, a chelator and achelated metal ion. It is further understood that the composition may bea prodrug comprising an antidiabetic agent conjugated to a chelator towhich a metal may be added. In such an embodiment, various metals may beadded to the composition as appropriate for different diagnostic ortherapeutic applications or for different types of imaging as describedherein. The use of compositions comprising metals or metal ions in thein vivo imaging of mammalian tissues or organs including human organs iswell known in the art, and any of such uses of an appropriate metal fora particular type of detection is contemplated by the presentdisclosure.

The compositions of the present disclosure may include, therefore,metals appropriate for contrast enhanced imaging or for scintigraphicimaging PET, MRI, or even CT imaging. The metal may be a radionuclide,including beta or gamma emitters, or it may be a magnetic orparamagnetic metal ion as needed. Preferred metals and metal ions foruse in the described compositions and methods include, but are notlimited to ions and isotopes of iron, manganese, chromium, copper,nickel, gadolinium, erbium, europium, dysprosium, holmium, gallium,germanium, cobalt, calcium, rubidium, yttrium, technetium, ruthenium,rhenium, indium, iridium, platinum, thallium, samarium, or boron, andmost preferred metal ions for imaging include technetium (Tc-99m),gallium (Ga-67, 68), copper (Cu-60-64), gadolinium (Gd), holmium(Ho-166), or holmium (Re-187, 188); preferred metal ions fortherapeutics include isotopes of yttrium, rhenium, copper and holmium.

The chelators of the disclosed compositions may be any appropriatechelators known in the art, including, but not limited todiethylenetriamine pentaacetic acid (DTPA), ethylene diaminetetra-acetic acid (EDTA), cyclohexyl 1,2-diamine tetra-acetic acid(CDTA), dimercaptosuccinic acid (DMSA), triglycinbenzoyl thiol (MAG-3),methylenebisphophonate (MDP), ethyleneglycol-0, 0′bis(2-aminoethyl)-N,N,N′,N′-tetra-acetic acid (EGTA),N,N-bis(hydroxybenzyl)-ethylenediamine-N,N′-diacetic acid (HBED),triethylene tetramine hexa-acetic acid (TTHA),1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid (DOTA),hydroxyethyldiamine triacetic acid (HEDTA), or1,4,8,11-tetra-azacyclo-tetradecane-N,N,N″,N′″-tetra-acetic acid (TETA).In the most preferred embodiments the chelator is DTPA.

The antidiabetic agents of the disclosed inventions may be anyantidiabetic drugs known in the art, or any compounds that bind to orassociate preferentially with beta cells of the pancreas. The mostpreferred agents are those that bind to a surface receptor on betacells, including various sulphonylurea receptors such as SUR-1, SUR2Aand SUR2B as well as other receptors such as the GLP-1 receptor or thesomatostatin receptor. Preferred antidiabetic agents includenateglinide, L-nateglinide, repaglinide, tolbutamide, glibenclamide,Amaryl, glipizide, glyburide, gliclazide, glimepiride, and mostpreferably nateglinide, glipizide, glyburide, or glimepiride.

In certain embodiments the compositions of the present inventions mayinclude any of the mentioned compounds or elements in any combination,and preferably include ^(99m)Tc-DTPA-nateglinide, ^(99m)Tc-DTPAglipizide, ^(99m)Tc-DTPA-glyburide or ^(99m)Tc-DTPA-glimepiride forgamma imaging.

In certain embodiments, the present invention may be described as amethod of treating a pancreatic disease comprising administering to asubject in need thereof a composition comprising an antidiabetic agent achelator and a chelated metal ion, wherein the metal ion is a betaemitter. A subject in need thereof may include any animal or humansubject that has, or is subject to developing a pancreatic diseaseincluding, but not limited to diabetes, pancreatitis, hyperinsulinemiaor insulinoma. Subjects may be identified by various methods known inthe clinical arts, including monitoring glucose tolerance, insulinresistance, blood insulin levels, blood glucose levels, majorhistocompatibility complex typing, certain antibodies, weight gain orloss, obesity, or even family history and genetic profiles.

Compositions as described herein are useful in a number of applications,both diagnostic, prognostic and therapeutic. As such, certainembodiments of the invention may be described as methods of imaging amammalian pancreas comprising administering to the mammal a compositioncomprising an antidiabetic agent, a chelator and a chelated metal ionand detecting an image of the pancreas. As described, the image may be agamma image, a PET image, an MRI image, or other types of images knownin the art.

Exemplary methods include methods of monitoring pancreatic beta cellmass or morphology in a mammal, useful for monitoring the condition ofthe pancreas in a susceptible subject prior to onset of a pancreaticdisease, or monitoring progress of a disease, or even methods ofmonitoring the outcome of certain therapies during treatment ormanagement of a pancreatic disease. The methods of the inventions may beused therefore to monitor beta cell mass, cell number, function, orlymphocyte infiltration into the beta cell mass.

Throughout this disclosure, unless the context dictates otherwise, theword “comprise” or variations such as “comprises” or “comprising,” isunderstood to mean “includes, but is not limited to” such that otherelements that are not explicitly mentioned may also be included.Further, unless the context dictates otherwise, use of the term “a” or“the” may mean a singular object or element, or it may mean a plurality,or one or more of such objects or elements.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1 is a synthetic scheme of metal-(^(99m)Tc, Gd) DTPA-NGN2.

FIG. 2 is ¹H-NMR spectrum of Nateglinide.

FIG. 3 is ¹H-NMR spectrum of NGN-Et.

FIG. 4 is ¹H-NMR spectrum of NGN-EA.

FIG. 5 is the Mass Spectrum of NGN-EA.

FIG. 6 is ¹H-NMR spectrum of NGN2.

FIG. 7 is the Mass Spectrum of DTPA-NGN2.

FIG. 8 is a synthetic scheme of DTPA-GLP.

FIG. 9 is ¹H-NMR data of Glipizide.

FIG. 10 is ¹H-NMR spectrum of Glipizide.

FIG. 11 is ¹³C-NMR data of Glipizide.

FIG. 12 is the ¹³C-NMR spectrum of Glipizide.

FIG. 13 is ¹H-NMR data of DTPA-Glipizide.

FIG. 14 is ¹H-NMR spectrum of DTPA-Glipizide.

FIG. 15 is ¹³C-NMR data of DTPA-Glipizide.

FIG. 16 is ¹³C-NMR spectrum of DTPA-Glipizide.

FIG. 17 is the Mass Spectrum of DTPA-Glipizide.

FIG. 18 is a synthetic scheme for DTPA-Glyburide.

FIG. 19 is the ¹H-NMR data of Glyburide.

FIG. 20 is the ¹H-NMR spectrum of Glyburide.

FIG. 21 is the ¹³C-NMR data of Glyburide.

FIG. 22 is the ¹³C-NMR spectrum of Glyburide.

FIG. 23 is the ¹H-NMR data of DTPA-Glyburide.

FIG. 24 is the ¹H-NMR spectrum of DTPA-Glyburide.

FIG. 25 is the ¹³C-NMR spectrum of DTPA-Glyburide.

FIG. 26 is a synthetic scheme for DTPA-GLMP.

FIG. 27 is ¹H-NMR data of GLMP.

FIG. 28 is a ¹H-NMR spectrum of GLMP.

FIG. 29 is ¹³C-NMR data of GLMP.

FIG. 30 is a ¹³C-NMR spectrum of GLMP.

FIG. 31 is ¹H-NMR data of DTPA-GLMP.

FIG. 32 is a ¹H-NMR spectrum of DTPA-GLMP.

FIG. 33 is ¹³C-NMR data of DTPA-GLMP.

FIG. 34 is a ¹³C-NMR spectrum of DTPA-GLMP.

FIG. 35 is ITLC data for Tc-DTPA-NGN2.

FIG. 36 is nuclear imaging of ^(99m)Tc-DTPA-Nateglinide. Mammarytumor-bearing rats were imaged with ^(99m)Tc-DTPA (left panel) and^(99m)Tc-DTPA-NGN2 (right panel) (300 μCi, i.v.). Selected planar imagesof ^(99m)Tc-DTPA-NGN2 are presented at 5 and 50 minutes post-injection.The arrow indicates the pancreas.

FIG. 37 is an image of a mammary tumor-bearing rat imaged with^(99m)Tc-DTPA-NGN2 (300 μCi, i.v.) Selected planar images of^(99m)Tc-DTPA-NGN2 are presented at 50 minutes post-injection. The arrowindicates the pancreas.

FIG. 38 is planar scintigraphy images of ^(99m)Tc-DTPA in 13762tumor-bearing rats (300 μCi/rat, i.v. injection).

FIG. 39 is planar scintigraphy images of ^(99m)Tc-DTPA-NGN (2) in 13762tumor-bearing rats (300 μCi/rat, i.v. injection).

FIG. 40 is planar scintigraphy images of ^(99m)Tc-DTPA-NGN (1) in 13762tumor-bearing rats (300 μCi/rat, i.v. injection).

FIG. 41 is images of breast tumor bearing rats imaged with ^(99m)Tc-DTPA(left panel), ^(99m)Tc-DTPA-NGN2 (middle panel) and^(99m)Tc-DTPA-NGN2with a blocking dose of 4 mg/kg NGN2 (right panel)(300 μCi, i.v.). Selected planar images are shown at 150 minutespost-injection.

FIG. 42 is images of breast tumor bearing rats imaged with ^(99m)Tc-DTPA(left panel), ^(99m)Tc-DTPA-NGN2 (middle panel) and ⁹⁹Tc-DTPA-NGN2 witha blocking dose of 4 mg/kg NGN2 (right panel) (300 μCi, i.v.). Selectedplanar images are shown at 150 minutes post-injection. The arrowindicates the pancreas.

FIG. 43 is planar scintigraphy images of ^(99m)Tc-DTPA and^(99m)Tc-DTPA-Glipizide (GLUCOTROL) in rats (300 μCi/rat, i.v.injection) at 5 minutes post injection.

FIG. 44 is planar scintigraphy images of ^(99m)Tc-DTPA and^(99m)Tc-DTPA-Glipizide (GLUCOTROL) in rats (300 μCi/rat, i.v.injection) at 15 minutes post injection.

FIG. 45 is planar scintigraphy images of ^(99m)Tc-DTPA in VX2tumor-bearing rabbits (1 mCi/rabbit, i.v. injection).

FIG. 46 is planar scintigraphy images of ^(99m)Tc-DTPA-NGN in VX2tumor-bearing rabbits (1 mCi/rabbit, i.v. injection). P indicates thepancreas.

FIG. 47 is a graphical representation comparing pancreas uptake for^(99m)Tc-DTPA and ^(99m)Tc-DTPA-NGN in breast tumor-bearing rats(n=3/time interval, 20 μCi, IV, p=0.11, 0.05, and 0.01).

FIG. 48 is a graphical representation of pancreas to muscle countdensity ratio of ^(99m)Tc-DTPA and ^(99m)Tc-NGN in breast tumor bearingrats (n=3/time interval, 20 μCi/rat, IV, p=0.19, 0.19, and 0.029).

DETAILED DESCRIPTION

The present disclosure provides compositions and methods to improve thediagnosis and treatment of pancreatic associated diseases including, butnot limited to diabetes, pancreatitis, insulinoma, adenocarcinoma, isletcell tumor, islet hypertrophy in diabetics and hyperinsulinemia based onthe discovery of compositions and methods for the imaging of beta cellsin vivo as well as the delivery of agents of therapeutic valuespecifically to pancreatic beta cells.

This disclosure is based on the development of compositions and methodsfor mechanism-based targeting of beta-cells for imaging and therapeuticpurposes. In preferred embodiments, the disclosed compositions includean antidiabetic agent, a chelator, and optionally a chelated metal ion.The present inventors have successfully demonstrated scintigraphicvisualization of the pancreas in rat and rabbit animal models using suchcompositions, including ^(99m)Tc-DTPA-nateglinide (NON) and^(99m)Tc-DTPA-glipizide.

The antidiabetic agents of the present disclosure are preferably agentsthat preferentially interact with or bind to specific receptors on thepancreatic beta cells. Such agents may bind to the sulphonylureareceptors, including SUR1, SUR2A and SUR2B, GLP-1 receptor, somatostatinreceptor, angiotensin II receptor, and/or bradykinin receptor. Preferredagents include, but are not limited to nateglinide, L-nateglinide,repaglinide, tolbutamide, glibenclamide, Amaryl, glipizide, glyburide,gliclazide, and glimepiride.

In certain preferred embodiments, the chelator of the disclosedcompositions is diethylenetriamine pentaacetic acid (DTPA). Otherchelators may also be used in the practice of the disclosure, includingbut not limited to ethylene diamine tetra-acetic acid (EDTA), cyclohexyl1,2-diamine tetra-acetic acid (CDTA), ethyleneglycol-0, 0′bis(2-aminoethyl)-N,N,N′,N′-tetra-acetic acid (EGTA),N,N-bis(hydroxybenzyl)-ethylenediamine-N,N′-diatetic acid (HBED),triethylene tetramine hexa-acetic acid (TTHA),1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA),hydroxyethyldiamine triacetic acid (HEDTA),1,4,8,11-tetra-azacyclo-tetradecane-N,N′,N″,N′″-tetra-acetic acid (TETA)dimercaptosuccinic acid (DMSA), triglycinbenzoyl thiol (MAG-3) andmethylenebisphophonate (MDP). The preferred metal ions for imaginginclude technetium (Tc-99m), gallium (Ga-67, 68), copper (Cu-60-64),gadolinium (Gd), holmium (Ho-166), or holmium (Re-187, 188); preferredmetal ions for therapeutics include yttrium, rhenium, copper andholmium.

Metal chelators useful in this disclosure include those which containcationic, basic and basic-amine groups and which chelate metals andmetal ions, transition elements and ions, and lanthanide series elementsand ions. It will be apparent to those skilled in the art thatessentially any single atomic element or ion amenable to chelation by acationic, basic and amine-containing chelator, may also be useful inthis disclosure.

Aqueous compositions of the present inventions comprise an effectiveamount of the described compositions dissolved and/or dispersed in apharmaceutically acceptable carrier and/or aqueous medium. The phrases“pharmaceutically and/or pharmacologically acceptable” refer tomolecular entities and/or compositions that do not produce an adverse,allergic and/or otherwise untoward reaction when administered to ananimal, and/or a human, as appropriate.

As used herein, “pharmaceutically acceptable carrier” includes anyand/or all solvents, dispersion media, coatings, antibacterial and/orantifungal agents, isotonic and/or absorption delaying agents and/or thelike. The use of such media and/or agents for pharmaceutical activesubstances is well known in the art. Except insofar as any conventionalmedia and/or agent is incompatible with the active ingredient, its usein the compositions is contemplated. Supplementary active ingredientscan also be incorporated into the compositions.

Aqueous carriers may include water, alcoholic/aqueous solutions, salinesolutions, parenteral vehicles such as sodium chloride, Ringer'sdextrose, etc. Intravenous vehicles may include fluid and nutrientreplenishers. Preservatives may include antimicrobial agents,anti-oxidants, chelating agents and inert gases. The pH and exactconcentration of the various components in the pharmaceutical areadjusted according to well known parameters.

For purposes of this disclosure, preferred metal ions are generallythose known in the art to be useful for imaging techniques including,but not limited to gamma scintigraphy, magnetic resonance, positronemission tomography, and computed tomography. Metal ions useful forchelation in paramagnetic T1-Type MRI contrast agent compositions anduses may include divalent and trivalent cations of metals selected fromiron, manganese, chromium, copper, nickel, gadolinium, erbium, europium,dysprosium and holmium. Chelated metal ions generally useful forradionuclide imaging and in radiotherapeutic compositions and uses, mayinclude metals selected from gallium, germanium, cobalt, calcium,rubidium, yttrium, technetium, ruthenium, rhenium, indium, iridium,platinum, thallium and samarium. Metal ions useful in neutron-captureradiation therapy may include boron and others with large nuclear crosssections. Metal ions useful in Ultrasound contrast and X-Ray contrastcompositions and uses may, provided they achieve adequate siteconcentrations, include any of the metal ions listed above, and inparticular, may include metal ions of atomic number at least equal tothat of iron.

The compositions may be provided “cold” (without a radioisotope label)or they may be provided with a label. Various radioactive labels may beused, as suited to a particular application. For example, a ^(99m)Tclabel may be preferred for gamma imaging, ⁶¹Cu— for PET imaging,gadolinium for MRI and ¹⁸⁸Re (¹⁶⁶Ho—) for internal radiotherapeuticapplications.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLE 1 Synthesis of DTPA-Nateglinide (DTPA-NGN)

DTPA-nateglinide was synthesized in a two-step manner. The syntheticscheme is shown in FIG. 1.

Step 1. Synthesis of Aminoethyl Amide Analogue of Nateglinide

Nateglinide (3.1742 g, 10 mmol) was dissolved in 20 mL of ethyl alcohol.Thionyl Chloride (5.1 mL, 70 mmol) was added dropwise to the solution.The reaction mixture was stirred overnight and the solvent wasevaporated at reduced pressure. FIGS. 2 and 3 showed ¹H-NMR ofnateglinide and its ester form.

Ethyl alcohol (20 mL) and ethylene diamine (3.4 mL, 50 mmol) were added.The mixture was stirred overnight. The solvent was evaporated at reducedpressure. The solid was dissolved in chloroform (50 mL) and washed withwater (2 ×50 mL). The chloroform layer was dried over anhydrousmagnesium sulfate. The solvent was filtered and evaporated at reducedpressure. Aminoethyl amide analogue of nateglinide was obtained as awhite solid (3.559 g, 99% yield). FIGS. 4 and 5 showed ¹HNMR and massspectrometry of aminoethyl amide analogue of nateglinide.

Step 2. Synthesis of DTPA-Nateglinide

Aminoethyl amide analogue of nateglinide (359.5 mg, 1.0 mmol) wasdissolved in DMSO (anhydrous, 10 ml). DTPA-dianhydride (178.7 mg, 0.5mmol) and triethyl amine (279 uL, 2.0 mmol) were added to the solutionand the mixture was heated at 60^(B)C for 4 hours. After cooling, water(8 mL) and 1N-sodium bicarbonate solution (8 mL) were added. The mixturewas stirred for 2 hours. The aqueous phase was dialyzed with membrane(MW CO<500) for 2 days. DTPA-NGN (413.9 mg, 87.7% yield) as a whitesolid was gathered after lyophilization. FIGS. 6 and 7 showed ¹H-NMR andmass spectrometry of DTPA-Nateglinide.

EXAMPLE 2 Synthesis of DTPA-Glipizide (DTPA-GLP)

Glipizide (445.5 mg, 1.0 mmol) was dissolved in DMSO (anhydrous, 10 ml).

Sodium amide (76.03 mg, 2.0 mmol) was then added. The reaction mixturewas stirred at room temperature for 10 min. DTPA-dianhydride (357.32 mg,1.0 mmol) was dissolved in DMSO (anhydrous, 10 ml). Sodium amide (76.03mg, 2.0 mmol) was then added. The reaction mixture was stirred at roomtemperature for 10 min. DTPA-dianhydride (357.32 mg, 1.0 mmol) dissolvedin 5 ml DMSO (anhydrous) was added and the mixture was stirred for 4hours. The mixture was added with water (10 mL), followed by 1N-sodiumhydroxide solution (3 mL) and stirred for 2 hours. The solid wasfiltered and washed with water. This recovered starting material was142.6 mg (32%) after drying under vacuum. The aqueous phase was dialyzedwith membrane (MW CO<500) for 2 days. DTPA-GLP (506.6 mg, ;61.7% yield)as a white solid was gathered after lyophilization. The synthetic schemeis shown in FIG. 8. FIGS. 9-17 showed ¹H-, ¹³C-NMR spectrum andassignment and mass spectrometry of DTPA-glipizide.

EXAMPLE 3 Synthesis of DTPA-Glyburide (DTPA-GLB)

Glyburide (494.0 mg, 1.0 mmol) was dissolved in DMSO (anhydrous, 5 ml).Sodium amide (195.0 mg, 5.0 mmol) was then added. The reaction mixturewas stirred at room temperature for 10 min. DTPA-dianhydride (357.32 mg,1.0 mmol) dissolved in 5 ml DMSO (anhydrous) was added and the mixturewas stirred for 22 hours. The dark green colored mixture was added withwater (10 mL), followed by 1N-sodium hydroxide solution (5 mL) andstirred for 2 hours. The solid was filtered and washed with water. Thisrecovered starting material was 88.9 mg (18%) after drying under vacuum.The aqueous phase was dialyzed with membrane (MW CO<500) for 2 days.DTPA-LB (695.5 mg, 80% yield) as a white solid was gathered afterlyophilization. The synthetic scheme is shown in FIG. 18. FIGS. 19-25showed ¹H-, ¹³C-NMR spectrum and assignment of glyburide andDTPA-glyburide.

EXAMPLE 4 Synthesis of DTPA-Glimepiride (DTPA-GLMP)

Glimepiride (490.6 mg, 1.0 mmol) was dissolved in DMSO (anhydrous, 10ml). Sodium amide (195.0 mg, 5.0 mmol) was then added. The reactionmixture was stirred at room temperature for 10 min. DTPA-dianhydride(357.32 mg, 1.0 mmol) dissolved in 5 ml DMSO (anhydrous) was added andthe mixture was stirred for 18 hours. The dark brown colored mixture wasadded with water (10 mL), followed by 1N-sodium hydroxide solution (5mL) and stirred for 2 hours. The solid was filtered and washed withwater. The aqueous phase was dialyzed with membrane (MW CO<500) for 2days. DTPA-GLMP (782.3 mg, 90.3% yield) was a white solid was gatheredafter lyophilization. The synthetic scheme is shown in FIG. 27. FIGS.28-34 showed ¹H-, ¹³C-NMR spectrum and assignment of glimepiride andDTPA-glimepiride.

EXAMPLE 5

Radiolabel DTPA-antidiabetic conjugates

Radiosynthesis of^(99m)Tc-DTPA-antidiabetic agents were achieved byadding the required amount of DTPA-antidiabetic agents (5-10 mg) and tin(II) chloride (SnCl₂, 100 _(μg)) and pertechnetate (Na^(99m)TcO₄, 5mCi). Radiochemical purity was assessed by radio-TLC (Bioscan,Washington, D.C.) using 1 M ammonium acetate: methanol (4:1) as aneluant. High-performance liquid chromatography (HPLC), equipped with aNal detector and UV detector (254 nm), was performed on a gel permeationcolumn (Biosep SEC-S3000, 7.8×300 mm, Phenomenex, Torrance Calif.) usinga flow rate of 1.0 ml/min. The eluant was 0.1% LiBr in phosphatebuffered saline (PBS 10 mM, pH=7.4). Radiochemical purity was <96% forall four agents. Radio-TLC data of ^(99m)Tc-DTPA-nateglinide is shown inFIG. 35.

EXAMPLE 6 Scintigraphic Imaging:

Scintigraphic imaging in rodents was conducted as follows:

Female Fischer 344 rates (150-175 g) (Harlan Sprague-Dawley, Inc.,Indianapolis, Ind.) were inoculated subcutaneously in the right leg withbreast cancer cells (10⁶ cells/rat) from the 13762 NF cell line (knownas DMBA-induced breast cancer cell line). Scintigraphic imaging wasserially performed on day 14 after inoculation. Planar images wereobtained at 0.5, 1 and 2 hours after injection of 300 μCi of^(99m)Tc-DTPA-NGN or ^(99m)Tc-DTPA-GLP via tail vein. Control groupswere given ^(99m)Tc-DTPA. Imaging was conducted with a gamma camera fromDigirad (2020tc Imager, San Diego, Calif.) equipped with a low-energyparallel-hole collimator. The field of view is 20 cm×20 cm with an edgeof 1.3 cm. The intrinsic spatial resolution is 3 mm and the matrix is64×64. The system is designed for a planar image with sensitivity of 56counts/second (cps)/MBq and spatial resolution of 7.6 mm. FIGS. 36-44showed that pancreas could be visualized with either^(99m)Tc-DTPA-nateglinide (NGN) or ^(99m)Tc-DTPA-glipizide in normal ratand tumor-bearing rats.

Scintigraphic imaging in rabbits was conducted as follows:

Male (n=4) New Zealand white rabbits (Raynichols Rabbitry, Lumberton,Tex.) were inoculated with VX-2 cells (rabbit driven mammary squamouscell carcinoma). At day 14 post-inoculation, scintigraphic imagingstudies were conducted with ^(99m)Tc-DTPA-NGN (1 mCi, iv). Computeroutlined region of interest was used to analyze target-to-nontargetratios. FIGS. 45 and 46 showed that pancreas could be visualized with^(99m)Tc-DTPA-nateglinide (NGN). FIGS. 47 and 48 showed that pancreasuptake was higher than control groups.

In summary, the imaging data demonstrated that the pancreas can beimaged with radiolabeled nateglinide and glipizide. Thus, uptake changesin pancreas can be assessed using this specific molecular marker.

All of the compositions and methods disclosed and claimed herein can bemade and executed without undue experimentation in light of the presentdisclosure. While the compositions and methods of this invention havebeen described in terms of preferred embodiments, it will be apparent tothose of skill in the art that variations may be applied to thecompositions and/or methods and in the steps or in the sequence of stepsof the methods described herein without departing from the concept,spirit and scope of the invention. More specifically, it will beapparent that certain agents which are both chemically andphysiologically related may be substituted for the agents describedherein while the same or similar results would be achieved. All suchsimilar substitutes and modifications apparent to those skilled in theart are deemed to be within the spirit, scope and concept of theinvention as defined by the appended claims.

1. A composition for imaging a pancreas comprising an antidiabeticagent, a chelator and a chelated metal ion.
 2. The composition of claim1, wherein the metal ion is effective for contrast enhanced imaging whenthe composition is administered to a mammal during use.
 3. Thecomposition of claim 1, wherein the chelator is diethylenetriaminepentaacetic acid (DTPA), ethylene diamine tetra-acetic acid (EDTA),cyclohexyl 1,2-diamine tetra-acetic acid (CDTA), ethyleneglycol-0, 0′bis(2-aminoethyl)-N,N,N′,N′-tetra-acetic acid (EGTA),N,N-bis(hydroxybenzyl)-ethylenediamine-N,N′-diacetic acid (HEED),triethylene tetramine hexa-acetic acid (TTHA),1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA),hydroxyethyldiamine triacetic acid (HEDTA),1,4,8,11-tetra-azacyclo-tetradecane-N,N′,N″,N′″-tetra-acetic acid(TETA), dimercaptosuccinic acid (DMSA), triglycinbenzoyl thiol (MAG-3)and methylenebisphophonate (MDP).
 4. The composition of claim 1, whereinthe chelator is DTPA.
 5. The composition of claim 1, wherein theantidiabetic agent binds preferentially to beta cells of the pancreas.6. The composition of claim 1, wherein the antidiabetic agent bindspreferentially to the pancreatic beta cell sulphonylurea receptor SUR-1,angiotensin II receptor, or bradykinin receptor.
 7. The composition ofclaim 1, wherein the antidiabetic agent is nateglinide, glipizide,glyburide, or glimepiride.
 8. The composition of claim 1, wherein themetal ion is a radionuclide.
 9. The composition of claim 1, wherein themetal ion is a beta emitter.
 10. The composition of claim 1, wherein themetal ion is a gamma emitter.
 11. The composition of claim 1, whereinthe metal ion is Tc-99m, Cu-60-64, Gd, Ho-166, or Re-187,
 188. 12. Thecomposition of claim 1, further defined as ^(99m)Tc-DTPA-nateglinide,^(99m)Tc-DTPA glipizide, ^(99m)Tc-DTPA-glyburide or^(99m)Tc-DTPA-glimepiride.
 13. A method of treating a pancreatic diseasecomprising administering to a subject in need thereof a compositioncomprising an antidiabetic agent, a chelator and a chelated metal ion,wherein the metal ion is a beta emitter.
 14. The method of claim 13,wherein the chelated metal ion is ¹⁸⁸Re ⁹⁰Y or ¹⁶⁶Ho.
 15. The method ofclaim 13, wherein the pancreatic disease is diabetes, pancreatitis,hyperinsulinemia or insulinoma.
 16. A method of imaging a mammalianpancreas comprising administering to the mammal a composition comprisingan antidiabetic agent, a chelator and a chelated metal ion, anddetecting an image of the pancreas.
 17. The method of claim 16, whereinthe image is a gamma image a PET image, or an MRI image.
 18. The methodof claim 16 wherein the composition comprises ^(99m)Tc-DTPA-nateglinide.19-38. (canceled)